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"Ferrari, Anthony"
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Conversations. Volume 3
Recorded during Borges' final years, this third volume of his conversations with Osvaldo Ferrari offers a rare glimpse into the life and work of Argentina's master writer and favourite conversationalist.
Book
Comprehensive characterization of claudin-low breast tumors reflects the impact of the cell-of-origin on cancer evolution
Claudin-low breast cancers are aggressive tumors defined by the low expression of key components of cellular junctions, associated with mesenchymal and stemness features. Although they are generally considered as the most primitive breast malignancies, their histogenesis remains elusive. Here we show that this molecular subtype of breast cancers exhibits a significant diversity, comprising three main subgroups that emerge from unique evolutionary processes. Genetic, gene methylation and gene expression analyses reveal that two of the subgroups relate, respectively, to luminal breast cancers and basal-like breast cancers through the activation of an EMT process over the course of tumor progression. The third subgroup is closely related to normal human mammary stem cells. This unique subgroup of breast cancers shows a paucity of genomic aberrations and a low frequency of
TP53
mutations, supporting the emerging notion that the intrinsic properties of the cell-of-origin constitute a major determinant of the genetic history of tumorigenesis.
Claudin-low tumors are a rare aggressive subtype of breast cancers. In this study, the authors use a multiomics approach to demonstrate that these tumors are heterogeneous and comprise three main subgroups that emerge from different evolutionary processes.
Journal Article
Interleukin-35 impairs human NK cell effector functions and induces their ILC1-like conversion with tissue residency features
Natural Killer (NK) cells play pivotal immunological roles including direct cytotoxic effector function and secretion of inflammatory and immunomodulating cytokines. In the context of chronic inflammation, NK cell fitness decreases during disease progression through currently unknown mechanisms. Here, we demonstrate that Interleukin-35 (IL-35) inhibits human NK cell proliferation, pro-inflammatory, and cytotoxic functions, while promoting secretion of TGF-β and proangiogenic factors in vitro. We show prolonged exposure to IL-35 converts both conventional and adaptive NK cells into CD9
+
CD103
+
CD49a
+
ILC1-like cells via autocrine TGF-β. We assess cancer patient-derived public datasets and reveal the presence of IL-35-producing cells and IL-35-receptor-expressing NK/ILC1-like cells within the tumor microenvironment and associate IL-35 with poor prognosis. Collectively, our findings identify and implicate IL-35 as a key driver of NK cell plasticity, promoting the acquisition of features associated with tissue residency and weakened effector functions, and could be relevant in pathophysiological contexts, highlighting IL-35 as an attractive target for future immunotherapies aimed at enhancing NK cell clinical activity.
Natural killer (NK) cells are critical innate immune effector cells but during chronic inflammatory contexts their function and fitness may become impaired. Here the authors implicate the cytokine IL-35 in the conversion of NK cells towards ILC1-like cells with features of tissue residency and impaired functionality.
Journal Article
A whole-genome sequence and transcriptome perspective on HER2-positive breast cancers
HER2-positive breast cancer has long proven to be a clinically distinct class of breast cancers for which several targeted therapies are now available. However, resistance to the treatment associated with specific gene expressions or mutations has been observed, revealing the underlying diversity of these cancers. Therefore, understanding the full extent of the HER2-positive disease heterogeneity still remains challenging. Here we carry out an in-depth genomic characterization of 64 HER2-positive breast tumour genomes that exhibit four subgroups, based on the expression data, with distinctive genomic features in terms of somatic mutations, copy-number changes or structural variations. The results suggest that, despite being clinically defined by a specific gene amplification, HER2-positive tumours melt into the whole luminal–basal breast cancer spectrum rather than standing apart. The results also lead to a refined
ERBB2
amplicon of 106 kb and show that several cases of amplifications are compatible with a breakage–fusion–bridge mechanism.
Breast cancer is separated into multiple subtypes based on the expression of HER2 and hormone receptors. Here, the authors report the whole genome sequence of 64 HER2 positive tumours and show that these can be further separated into four groups with different gene expression profiles and genomic features.
Journal Article
Comprehensive molecular portrait reveals genetic diversity and distinct molecular subtypes of small intestinal neuroendocrine tumors
Small intestinal neuroendocrine tumors (siNETs) are rare bowel tumors arising from malignant enteroendocrine cells, which normally regulate digestion throughout the intestine. Though infrequent, their incidence is rising through better diagnosis, fostering research into their origin and treatment. To date, siNETs are considered to be a single entity and are clinically treated as such. Here, by performing a multi-omics analysis of siNETs, we unveil four distinct molecular groups with strong clinical relevance and provide a resource to study their origin and clinical features. Transcriptomic, genetic and DNA methylation profiles identify two groups linked to distinct enteroendocrine differentiation patterns, another with a strong immune phenotype, and the last with mesenchymal properties. This latter subtype displays the worst prognosis and resistance to treatments in line with infiltration of cancer-associated fibroblasts. These data provide insights into the origin and diversity of these rare diseases, in the hope of improving clinical research into their management.
Small intestinal neuroendocrine tumours (siNETs) are rare bowel tumors generally considered to be a single entity. Here, the authors perform a multiomics analysis of siNETs and reveal four distinct molecular groups with clinical relevance, including groups linked to differentiation patterns, immunity, and mesenchymal properties.
Journal Article
Immunomic longitudinal profiling of the NeoPembrOv trial identifies drivers of immunoresistance in high-grade ovarian carcinoma
PD-1/PD-L1 blockade has so far shown limited survival benefit for high-grade ovarian carcinomas. By using paired samples from the NeoPembrOv randomized phase II trial (NCT03275506), for which primary outcomes are published, and by combining RNA-seq and multiplexed immunofluorescence staining, we explore the impact of NeoAdjuvant ChemoTherapy (NACT) ± Pembrolizumab (P) on the tumor environment, and identify parameters that correlated with response to immunotherapy as a pre-planned exploratory analysis. Indeed, i) combination therapy results in a significant increase in intraepithelial CD8
+
PD-1
+
T cells, ii) combining endothelial and monocyte gene signatures with the
CD8B/FOXP3
expression ratio is predictive of response to NACT + P with an area under the curve of 0.93 (95% CI 0.85-1.00) and iii) high
CD8B/FOXP3
and high
CD8B/ENTPD1
ratios are significantly associated with positive response to NACT + P, while
KDR
and VEGFR2 expression are associated with resistance. These results indicate that targeting regulatory T cells and endothelial cells, especially VEGFR2
+
endothelial cells, could overcome immune resistance of ovarian cancers.
Changes in the tumour microenvironment have been associated with response and resistance to immunotherapy. Here, by performing longitudinal transcriptomic and spatial analysis, the authors report the exploratory analysis of their phase II trial of neoadjuvant chemotherapy alone or in combination with pembrolizumab (anti-PD1) in patients with advanced high-grade ovarian carcinoma.
Journal Article
Partially methylated domains are hypervariable in breast cancer and fuel widespread CpG island hypermethylation
Global loss of DNA methylation and CpG island (CGI) hypermethylation are key epigenomic aberrations in cancer. Global loss manifests itself in partially methylated domains (PMDs) which extend up to megabases. However, the distribution of PMDs within and between tumor types, and their effects on key functional genomic elements including CGIs are poorly defined. We comprehensively show that loss of methylation in PMDs occurs in a large fraction of the genome and represents the prime source of DNA methylation variation. PMDs are hypervariable in methylation level, size and distribution, and display elevated mutation rates. They impose intermediate DNA methylation levels incognizant of functional genomic elements including CGIs, underpinning a CGI methylator phenotype (CIMP). Repression effects on tumor suppressor genes are negligible as they are generally excluded from PMDs. The genomic distribution of PMDs reports tissue-of-origin and may represent tissue-specific silent regions which tolerate instability at the epigenetic, transcriptomic and genetic level.
In cancer, global DNA methylation loss and CpG island hypermethylation are commonly observed. Here, in breast cancer the authors find that hyper-variability of partially methylated domains is the prime source of DNA methylation variation and that these domains fuel CpG island hypermethylation.
Journal Article
Microwave-Assisted Superheating and/or Microwave-Specific Superboiling (Nucleation-Limited Boiling) of Liquids Occurs under Certain Conditions but is Mitigated by Stirring
Temporary superheating and sustained nucleation-limited “superboiling” of unstirred liquids above the normal atmospheric boiling point have been documented during microwave heating. These phenomena are reliably observed under prescribed conditions, although the duration (of superheating) and magnitude (of superheating and superboiling) vary according to system parameters such as volume of the liquid and the size and shape of the vessel. Both phenomena are mitigated by rapid stirring with an appropriate stir bar and/or with the addition of boiling chips, which provide nucleation sites to support the phase-change from liquid to gas. With proper experimental design and especially proper stirring, the measured temperature of typical organic reaction mixtures heated at reflux will be close to the normal boiling point temperature of the solvent, whether heated using microwave radiation or conventional convective heat transfer. These observations are important to take into consideration when comparing reaction rates under conventional and microwave heating.
Journal Article
The NF-κB RelA transcription factor is not required for CD8+ T-cell function in acute viral infection and cancer
CD8 + T cells are critical mediators of pathogen clearance and anti-tumor immunity. Although signaling pathways leading to the activation of NF-κB transcription factors have crucial functions in the regulation of immune responses, the CD8 + T cell-autonomous roles of the different NF-κB subunits, are still unresolved. Here, we investigated the function of the ubiquitously expressed transcription factor RelA in CD8 + T-cell biology using a novel mouse model and gene-edited human cells. We found that CD8 + T cell-specific ablation of RelA markedly altered the transcriptome of ex vivo stimulated cells, but maintained the proliferative capacity of both mouse and human cells. In contrast, in vivo experiments showed that RelA deficiency did not affect the CD8 + T-cell response to acute viral infection or transplanted tumors. Our data suggest that in CD8 + T cells, RelA is dispensable for their protective activity in pathological contexts.
Journal Article
High-Resolution Comparative Genomic Hybridization of Inflammatory Breast Cancer and Identification of Candidate Genes
Inflammatory breast cancer (IBC) is an aggressive form of BC poorly defined at the molecular level. We compared the molecular portraits of 63 IBC and 134 non-IBC (nIBC) clinical samples.
Genomic imbalances of 49 IBCs and 124 nIBCs were determined using high-resolution array-comparative genomic hybridization, and mRNA expression profiles of 197 samples using whole-genome microarrays. Genomic profiles of IBCs were as heterogeneous as those of nIBCs, and globally relatively close. However, IBCs showed more frequent \"complex\" patterns and a higher percentage of genes with CNAs per sample. The number of altered regions was similar in both types, although some regions were altered more frequently and/or with higher amplitude in IBCs. Many genes were similarly altered in both types; however, more genes displayed recurrent amplifications in IBCs. The percentage of genes whose mRNA expression correlated with CNAs was similar in both types for the gained genes, but ∼7-fold lower in IBCs for the lost genes. Integrated analysis identified 24 potential candidate IBC-specific genes. Their combined expression accurately distinguished IBCs and nIBCS in an independent validation set, and retained an independent prognostic value in a series of 1,781 nIBCs, reinforcing the hypothesis for a link with IBC aggressiveness. Consistent with the hyperproliferative and invasive phenotype of IBC these genes are notably involved in protein translation, cell cycle, RNA processing and transcription, metabolism, and cell migration.
Our results suggest a higher genomic instability of IBC. We established the first repertory of DNA copy number alterations in this tumor, and provided a list of genes that may contribute to its aggressiveness and represent novel therapeutic targets.
Journal Article